Percutaneous administration of physiologically active ingredients has been carried out in order to produce topical effects on the skin or subcutaneous tissues beneath the skin. Examples of such topical effects include sterilization, disinfection, analgesia, anti-pruritus, anti-inflammation and the like.
On the other hand, oral or intravenous administration of physiologically active ingredients has been carried out in order to produce systemic effects in the subject.
Oral administration is disadvantageous in that the physiologically active ingredients so administered are susceptible to first-order metabolism in the liver. Further, in order to obtain a long-lasting effect, the concentration of the physiologically active ingredients must be initially higher than is normally necessary for effectiveness. In addition, oral administration of some physiologically active ingredients, like indomethacin, causes gastrointestinal side effects.
Intravenous administration, although advantageous for obtaining rapid absorption of the physiologically active ingredients disadvantageously requires a specialist, such as a physician.
Recently, methods for achieving systemic effects in a subject through percutaneous administration of physiologically active ingredients have been proposed in order to overcome the above-described problems associated with oral and intravenous administration of physiologically active ingredients. Percutaneous administration of physiologically active ingredients has the following advantages:
(1) the physiologically active ingredients enter from the skin directly into the blood stream and are not, therefore, susceptible to first-order metabolism in the liver, PA1 (2) the release of the physiologically active ingredients can be easily sustained, and PA1 (3) the concentration of the physiologically active ingredients in the subject is controllable. PA1 (A) a pharmaceutically effective amount of a physiologically active ingredient, and PA1 (B) a percutaneous absorption enhancing effective amount of a member selected from the group consisting of an anti-histamine, an anti-depressant, a vasodilator, an anti-psychotic, an anesthetic and an analgesic, PA1 (A) a pharmaceutically effective amount of a physiologically active ingredient, and PA1 (B) a percutaneous absorption enhancing effective amount of a member selected from the group consisting of an anti-histamine, an anti-depressant, a vasodilator, an anti-psychotic, an anesthetic and an analgesic,
However, the stratum corneum has long been considered a major barrier to the penetration of physiologically active ingredients (Marzulli, A. N., J. Invest. Dermatol., 39:387-393 (1963)). Studies have shown that most physiologically active ingredients have a low permeability through skin. As a result, transdermal drug delivery systems have been utilized to accelerate the permeability of physiologically active ingredients through skin (Gummer, C. L., Percutaneous Absorption, Eds. Bronaugh, R. L. et al, Mercel Dekker Inc., New York, pages 561-570 (1985)).
Percutaneous delivery enhancers may offer a means of increasing penetration of physiologically active ingredients. For example, organic solvents such as ethanol, propylene glycol, pyrrolidones, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, alkyl sulfoxide, phosphine oxide, sugar esters and surfactants are well known percutaneous delivery enhancers (Barry, B. W., Dermatological Formulations, Marcel Dekker Inc., New York, pages 160-172 (1983)). One enhancer, 1-dodecylazacycloheptan-2-one (Azone), has been shown to increase the absorption of antibacterial agents, antifungal agents, steroids, iododeoxyuridine and 5-fluorouracil (Stoughton, R. B., Arch. Dermatol., 118:474-477 (1982); Stoughton, R. B. et al, Drug Dev. Ind. Pharm., 9:725-744 (1983); Chow, D. S-L. et al, J. Pharm. Sci., 73:1794-1799 (1984); Wotton, P. K. et al, Int. J. Pharm., 24:19-26 (1985); Barry, B. W., J. Contr. Rel., 6:85-97 (1987); and Barry, B. W. et al, J. Pharm. Pharmacol., 39:535-546 (1987)). To date, the mechanism of Azone's action is not well understood. However, it is believed that the site of action is the stratum corneum (Sugibayashi, K. et al, J. Pharm. Sci., 37:578-580 (1985)). Azone is minimally absorbed and that which is absorbed is removed rapidly from circulation (Wiechers, J. W. et al, Pharm. Res., 4:519-523 (1987)).
In addition, is has been reported that the transport of salicylic acid and acyclovir through skin can be increased by the addition of small amounts of fatty acids or alcohols (Cooper, E. R., J. Pharm. Sci., 73:1153-1156 (1984); and Cooper, E. R. et al, J. Pharm. Sci., 74:688-689 (1985)).
The enhancing effect of N-decylmethyl sulfoxide on skin permeation of 5-fluorouracil has also been reported (Touitou, E. et al, Int. J. Pharm., 27:89-98 (1985)).
Moreover, the enhancing effects of several amides of cyclic amines through hairless mouse skin have been reported (Mirejovsky, D. et al, J. Pharm. Sci., 75:1089-1093 (1986)). Enhancers containing an azacyclo ring and terpene chain have been found to promote mitocymin C penetration through hairless mouse and rat skin (Okamoto, H. et al, J. Pharm. Pharmacol., 39:531-534 (1987)).